Unusual clinical features and histopathological findings in a case of Pseudo-endophthalmitis in neovascular glaucoma

Objective: This case report aimed to describe the unusual clinical presentation and histopathological features of post-injection endophthalmitis. Methods: A 56-year-old male phakic patient with diabetic retinopathy received an intravitreal injection (Bevacizumab as per the patient) for neovascular glaucoma elsewhere and presented to our center one day after the dose with hypopyon. The eye was relatively white without pain or lid oedema. The patient was treated as a case of post-injection endophthalmitis with two doses of intravitreal antibiotics 48 hours apart. During the follow-up, he developed a Covid infection. After one week, when the media cleared, white exudates were seen in the vitreous cavity with a relatively healthy retina. He was taken up for pars plana vitrectomy and vitreous biopsy for histopathological study. Results: The microscopic examination of vitreous aspirate revealed crystalline deposits without any microorganisms. Two control slides, one with a mixture of intravitreal antibiotics, which were previously injected, and the other with fresh Triamcinolone were also examined. Although the findings of the drug mixture did not match the vitreous aspirate, they matched with triamcinolone, which established it as a case of pseudo endophthalmitis due to triamcinolone injected elsewhere. Discussion: Initially, it seemed like a straightforward case of post-injection endophthalmitis, but a further examination of the vitreous aspirate showed that it was pseudoendophthalmitis due to an intravitreal triamcinolone injection. Despite the patient being phakic, neovascularization or elevated intraocular pressure may have led to the disruption of the blood-ocular barrier and the migration of Triamcinolone into the anterior chamber. Conclusion: The case’s uniqueness lies in being the first reported case of pseudo endophthalmitis in a phakic patient with an intact lens iris diaphragm. The case also highlighted the judicious use of available resources and out-of-the-box thinking to reach a diagnosis that may not always be obvious. Abbreviations: TA = Triamcinolone acetonide, AC = Anterior chamber, IVB = Intravitreal Bevacizumab, PL = Perception of light


Introduction
Intravitreal injections have gained popularity in the management of various retinal diseases.One of the dreaded complications is endophthalmitis and the projected incidence of acute post-injection endophthalmitis following intravitreal bevacizumab and triamcinolone is approximately 0.066% and 0.10-0.87%respectively, despite using maximal sterile precautions [1,2].
The incidence of non-infectious endophthalmitis after intravitreal triamcinolone has been reported to range from 0.2% to 1.6% in various series [2].Pseudo endophthalmitis indicates the dispersion of drug crystals in the anterior chamber (AC) closely mimicking infectious endophthalmitis [3].The benzyl alcohol preservative in the preparation has been speculated to be a stimulus for the inflammatory reaction, however, rarely, preservative-free Triamcinolone acetonide (TA) crystals causing pseudo endophthalmitis have been reported in the literature [4,5].
The diagnosis of pseudo-endophthalmitis is straightforward if the offending drug has been injected intraocularly, however, in this case, the patient was treated elsewhere, having a history of intravitreal Bevacizumab (IVB) injection.As per the protocol, he was initially managed as a case of postinjection endophthalmitis, however, the microscopic of vitreous aspirate for drug crystals unraveled the mystery.

Material and methods
A 54-year-old male diagnosed with a case of proliferative diabetic retinopathy with neovascular glaucoma in both eyes presented to our institute with complaints of gross painless diminution of vision in the left eye.According to his history, intravitreal Bevacizumab 0.05 ml was administered in the left eye elsewhere.On examination, the BCVA of both eyes was Perception of light (PL) +.
There was no lid edema, and the eye was white, however, anterior segment examination revealed 4+ cells and a mobile hypopyon (Fig. 1 A, B).The fundus glow was poor, and the fundus details were hazy.Intraocular pressure was 28 mmHg.Ocular ultrasound B Scan revealed clump-like vitreous echoes.A provisional diagnosis of acute post-injection endophthalmitis in the left eye was made.As the patient was practically one-eyed, he was planned for an anterior chamber paracentesis followed by administration of intravitreal Vancomycin (1 mg/0.1 ml) and Ceftazidime (2.5 mg/0.1 ml).The microbiological examination of the aqueous sample did not reveal any microorganisms.
The patient did not complain of any pain on postoperative day 1 and his best corrected visual acuity (BCVA) was PL+ and there was no significant change in the anterior segment findings.To complicate the ease of workup and follow-up, the patient tested positive for COVID-19.He was continued on topical anti-glaucoma medication, steroids, and antibiotics.According to the protocol, the intraocular antibiotics were repeated after 48 hours as no response was appreciated clinically, and the B scan echoes persisted.The patient continued to be pain-free with a persistent decrease in visual acuity.He was extensively investigated for the possibility of endogenous endophthalmitis including a blood and urine culture, however, all the relevant test results were negative.
On day 7, the anterior chamber was quiet and the hypopyon had disappeared with the persistence of an abnormal white fundal glow with whitish clumped exudates in the superotemporal quadrant.Further evaluation was needed, as the patient's visual acuity had not improved and a suspicious coagulum obscuring the posterior segment was present, in addition to his one-eyed status.There were two possibilities at that juncture, one was endogenous fungal endophthalmitis given the patient's uncontrolled hyperglycemia or pseudo endophthalmitis or a drug coagulum based on focal, curdy white non-progressive nature.
To unravel the mystery, a 23 G pars plana vitrectomy with vitreous biopsy was performed to confirm the cause of the enigmatic coagulum.Intraoperatively, the exudate was noted to be clumpy, intermeshed with the vitreous gel, and localized without involving the rest of the retina (Fig. 1 C, D).The coagulum could be due to previous intravitreal injections, although antibiotics were given with separate syringes.The microscopy of the coagulum was done not only for microorganisms but also for drug crystals.The microbiologist was also surprised at the unusual demand.The microscopy of the smear revealed polygonal crystals (Fig. 2 A

Discussion
At the outset, the case appeared like a straightforward case of post-intravitreal injection endophthalmitis, however, after microscopy of vitreous revealing TA crystals, pseudo endophthalmitis attributable to intravitreal triamcinolone (IVTA) became evident.Culture-proven endophthalmitis is a potential complication of intravitreal injections.In our case, initially, there was a clear history of bevacizumab injection, and the signs justified it to be a case of post-injection endophthalmitis.The only point against it was the lack of pain, which we reconsidered and paid heed to when the microbiological investigations were negative for any growth.History of visual loss immediately or soon after injection of TA, presence of a hypopyon, anterior or vitreous inflammation, and triamcinolone crystals in the anterior or posterior chambers can aid the identification of non-infectious endophthalmitis [2].
We administered intravitreal antimicrobials to the patient but saw a surprising regression of hypopyon without improvement in media clarity, or BCVA.As the media cleared and we noted a persistent white coagulum, obscuring the posterior pole, we chose to do PPV with a vitreous biopsy given the patient's gross reduction in vision.The vitreous tap was sent specially to rule out any negative fungal pathogen.We decided to explore the other end of the spectrum of pseudo-endophthalmitis.The vitreous tap revealed crystals like those of triamcinolone.The patient had also received intravitreal antibiotics, so a control slide was prepared with a mixture of vancomycin + Ceftazidime to rule out similar crystals.The histopathological study clinched the diagnosis of pseudo endophthalmitis due to TA.
Another retrospective case series including 4 patients reported an endophthalmitis-like reaction following an IVTA.There was a dense vitreous haze with a severe reduction of fundus view in all cases as was also a finding in our case [6,7].
Pseudo-endophthalmitis post-IVTA is a distinct clinical entity that may resolve without specific treatment [6].Critical judgment by the clinician to diagnose this condition may avoid unnecessary invasive treatments.In this case, a strong clinical suspicion was the key to diagnosis despite a disconnected history.The vitrectomy and removal of TA in this case might have helped in reducing the IOP as such the patient had neovascular glaucoma.
It is well reported in the literature that anterior migration of TA can occur in eyes lacking a capsular barrier, which allows direct communication between the vitreous cavity and the anterior chamber [8].Our case is unique in the sense that it is the first reported case of pseudo endophthalmitis in a phakic patient with intact lens iris diaphragm and baffled us as to how the triamcinolone injected intravitreally migrated to the anterior chamber.The possible

BFig. 1 AFig. 2 AB
Fig. 1 A, B Anterior segment findings revealing Hypopyon and 4+ cells; C, D. Intraoperative view, whitish exudate noted to be clumpy, intermeshed with vitreous gel, and localized without involving the rest of the retina

Fig. 3 A
Fig. 3 A The Triamcinolone sample revealed boxshaped, polygonal well-defined crystals like those noted in the coagulum; B. A combination of vancomycin and ceftazidime devoid of clear-cut crystals